Folinic Acid, Cerebral Folate Deficiency and Autism FAQ

This guide answers common questions about folinic acid (leucovorin) therapy, cerebral folate transport deficiency (CFD) and folate receptor antibodies. 

What is folate?

Folate is a type of vitamin B that our bodies need. It helps cells function and keeps the brain healthy. Folate enters the brain with the help of a folate transporter called the cerebral folate receptor. The cerebral folate receptor protein is made by a gene called FOLR1. When the brain does not receive enough folate, this is called Cerebral Folate Transport Deficiency (CFD). CFD can occur when the gene FOLR1 stops working. Genetic testing can identify differences in the FOLR1 gene that cause it to stop working. 

What is Cerebral Folate Transport Deficiency (CFD) genetic disorder?

This is a very rare genetic condition caused by changes in a gene called FOLR1. The gene helps make a protein that moves folate into the brain. If this gene is not working, the brain does not receive enough folate. This can sometimes lead to behavior signs that look like autism.

Children with this disorder may have trouble walking, talking or learning. Children with mutations in FOLR1 often develop symptoms like intellectual disability, speech difficulties, seizures, trouble with coordination (ataxia), weak muscles (hypotonia), tremors and sometimes behaviors present in autistic individuals.

If your child has these symptoms, genetic testing is recommended to check for this disorder. 

Is CFD associated with autism?

CFD is not present in all autistic individuals, but it can lead to behavior signs that look like autism. Fewer than 50 cases have been documented in the medical literature, which means that it happens less often than one in a million. This makes this genetic condition ultrarare. Children with changes in the FOLR1 gene often have delays and autistic features because their brain lacks folate. It is so rare that most autistic children will not carry changes in this gene.

How do you get tested for CFD?

This needs a genetic test done in a specific lab. A doctor takes a blood or spit sample and looks at the FOLR1 gene for changes. If found, it can explain why the brain lacks folate. This condition can also be diagnosed by measuring folate levels in brain fluid collected through a needle inserted in the lower part of the back.

My child already had genetic testing, and it was negative. Does that mean that my child was tested for CFD?

If your child had an autism gene/intellectual disability gene panel, exome sequencing or genome sequencing test, they have already been tested for FOLR1. If you would like to pursue additional genetic testing or discuss the most comprehensive testing options available currently, please call 310-206-6581 to schedule an appointment. 

What are folate receptor antibodies?

Folate receptor antibodies are protein blockers in the blood that can stop folate from entering the brain. This has been proposed as another cause of cerebral folate transport deficiency, where the brain does not receive enough folate. Some autistic children have these antibodies, but nonautistic children can have them as well. 

Are folate receptor antibodies associated with autism?

It is not clear if they are associated with autism and scientists are still studying this. Many autistic children have these antibodies. One study found that over 75% of autistic children had them, however 10-15% of healthy children did have them as well. These antibodies can block folate from entering the brain, which might lead to brain problems like those in autism. Children with these antibodies often show certain behaviors linked to autism, like trouble talking or being social. However, these findings are still preliminary and not all studies agree. One study showed that autistic boys had fewer of these antibodies than healthy boys. Having folate receptor antibodies does not always mean a child is autistic. It might just be a chance association, not a direct link. Autism has many known associations, including changes in hundreds of genes and in some cases environmental exposures.

How can I test my autistic child for folate receptor antibodies?

You can do a blood test called the FRAT test. It checks for these antibodies in the blood. Only a doctor can order it, and it requires a blood sample sent to a specific lab. The test shows if there are blocking or binding antibodies that might stop folate from reaching the brain. It is not a test for autism itself. 

What is folinic acid?

Folinic acid is a special form of folate. It is also called leucovorin. It can get into the brain in a different way, even if the folate receptor does not work.

Is folinic acid a therapy for autistic children with folate receptor antibodies?

Folinic acid has not been approved for the use of cerebral folate deficiency. Some doctors use it off label, meaning it’s not approved to treat autism yet. Small studies have shown it may improve communication in some children with high folate receptor antibodies. However, other studies have not confirmed these results, and larger studies are needed to prove it works in autistic children. 

Should I try folinic acid for my autistic child?

Currently, the Society for Inborn Errors of Metabolism, American Academy of Neurology, Autism Speaks, and the International Society for Autism Research all suggest that we wait for additional studies before we recommend folinic acid therapy for autistic children. The FDA has announced that it will be relabeling the indications for using leucovorin to include patients with CFD due to a genetic condition. The FDA finds that “CFD has also been reported in a broader patient population with neuropsychiatric symptoms, including autistic features, and detectable serum autoantibodies to the folate receptor alpha; however, there are limitations on the available data for the use of leucovorin in this population and additional studies are needed to assess safety and efficacy.” (https://www.fda.gov/news-events/press-announcements/fda-takes-action-make-treatment-available-autism-symptoms).

At this time the UCLA Division of Clinical Genetics, in accordance with FDA guidelines and existing professional societies, will not be offering FRAT testing or offering leucovorin therapy except for patients with a documented FOLR1 genetic condition and after FDA approval for such indication. 

Every autistic child is different, and we are here to help provide clinical diagnoses that open the opportunity to promote healthier lives. As more research takes place and we learn more, stay updated with trusted sources like the UCLA Division of Clinical Genetics.